Multi-Modal Treatment Of Calciphylaxis With Sodium

Transcription

Kidney Blood Press Res 2013;37:346-359
DOI: 10.1159/000350162
Published online: September 22, 2013
© 2013 S. Karger AG, Basel
www.karger.com/kbr
Salmhofer/Franzen/Hitzl/Koller/Kreymann/Fend/Hauser-Kronberger/Heemann/Berr/
Accepted:
August 02, 2013
1423-0143/13/0375-0346$38.00/0
Schmaderer: Triple Treatment of Calciphylaxis
This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to
the online version of the article only. Distribution permitted for non-commercial purposes only.
Original Paper
Multi-Modal Treatment Of Calciphylaxis
With Sodium-Thiosulfate, Cinacalcet And
Sevelamer Including Long-Term Data
Hermann Salmhofera,b Michael Franzena,b Wolfgang Hitzlc Josef Kollerd
Bernhard Kreymannb Falko Fende Cornelia Hauser-Kronbergerf
Uwe Heemannb Frieder Berra Christoph Schmadererb
a
Nephrology Unit, 1st Medical Department, Paracelsus Medical University, Salzburg; bNephrology Unit,
2nd Medical Department, Technical University of Munich; cResearch Office, Biostatistics, Paracelsus
Medical University, Salzburg; dDepartment of Dermatology, Paracelsus Medical University, Salzburg;
e
Department of Pathology, Technical University of Munich; fDepartment of Pathology, Paracelsus
Medical University Salzburg
Key Words
Calciphylaxis • Calcific uremic arteriolopathy • End stage renal disease • Hyperparathyroidism
• Sodium thiosulfate • Cinacalcet • Sevelamer
Abstract
Background: Calciphylaxis is a rare, yet life-threatening disease mainly occurring in dialysis
patients. Traditional options of treatment remain unsatisfactory. Methods: Here we present a
novel, combined approach, treating calciphylaxis with IV sodium thiosulfate, cinacalcet and
sevelamer. In a case series five hemodialysis patients, have been successfully treated with this
regimen. Treatment and survival data were analyzed using descriptive statistics. Results: In all
patients, a rapid decrease in pain, improvement of general condition and wound healing within
six months occurred. Side effects were low. Drug dosages: IV sodium thiosulfate initial dose
119.4 +/- 84.9 g/m2/week, maintenance dose 40.6 +/- 9 g/m2/week; cinacalcet: maintenance
dose 36 +/- 32.9 mg/d and sevelamer maintenace dose 3320 +/-1671 mg/d. One and two
year survivals were 100 % and 80 %, respectively. We also report on long-term application of
IV sodium thiosulfate of up to 52 months. Patient survival after diagnosis was 52, 84, 21, 36
and 30 months, respectively. Survival since initiation of hemodialysis was 76, 136, 89, 36 and
35 months, respectively. Conclusion: This novel combined approach, a multi-modal treatment
of calciphylaxis with persistent hyperparathyroidism, using IV sodium thiosulfate, cinacalcet
and sevelamer seems to improve the outcome of this devastating disease.
Copyright © 2013 S. Karger AG, Basel
Dr. Hermann Salmhofer
Nephrology Unit, Department of Internal Medicine I, LKH-Universitätsklinikum
Salzburg, Müllner Hauptstraße 48, A-5020 Salzburg (Austria)
Tel. 0043-662-4482-58487, Fax 0043-662-4482-881, E-Mail [email protected]
346
DOI: 10.1159/000350162
www.karger.com/kbr
Introduction
Calciphylaxis is a rare disease mainly occuring in dialysis patients with renal
hyperparathyroidism [1]. Additionally, calciphylaxis has been seen in other conditions,
especially during coumadin treatment [2-4]. Medial and luminal calcification of small
cutaneous and subcutaneous arterial vessels leads to vascular thrombosis and occlusion,
consequent ischemia, necrosis, infection and – in most cases – death within weeks to months
[5-7]. Mortality rates are estimated at 60-80 % [8]. Several variations of the disease may
occur: cutaneous (necrotizing; including an acral subtype), subcutaneous (non-necrotizing)
and systemic forms (involving vessels of internal organs, such as gut, heart and brain) [9, 10].
Apart from vessel calcification and tissue calcification, septal panniculitis can be found in a
subgroup of patients [11].
For decades there has been speculation about pathogenetic factors and triggers of
the disease [6]. Contributing factors include: end-stage renal disease, dialysis treatment,
hyperphosphatemia, hypercalcemia, increased calcium-phosphate product, increased levels
of parathyroid hormone, vitamin D supplementation, increased calcium load by calciumcontaining phosphate binders, coumadin treatment, diabetes mellitus, tissue trauma, female
gender, morbid obesity, rapid weight loss, malnutrition, low plasma albumin, steroid or
immunosuppressive treatment, substitution of blood products and inflammation; for review
see [12, 13]. It is as yet unclear, whether calciphylaxis follows a similar pathogenesis as the
calcifying vasculopathy of patients with end stage renal disease, which includes an active
transdifferentiation of vascular smooth muscle cells to an osteoblast phenotype [14].
Diagnosis usually is made clinically. Consideration of predisposing conditions, risk factors
and alertness to ‘warning signals’ (extreme pain, livid cutaneous nodules and indurations,
livedo sign, typical bizzare configuration of skin ischemia and necrosis) are generally
sufficient to characterize the disease [15]. Skin biopsy, although desirable, frequently has
been avoided, since progressive skin necrosis may be precipitated at the biopsy site.
Treatment up to now has been unsatisfactory. Different approaches have been suggested,
including emergency parathyroidectomy [16], extensive dialysis against low calcium levels
[17], bisphosphonates [18], cessation of steroids and immunosuppressants [19], optimum
phosphate control using calcium and aluminium free phosphate binders [20] as well as use
of prostaglandin and hyperbaric oxygenation [21].
Unequivocally, prognosis of this disease has been grim [22]. Two new principles of
treatment have recently emerged: (i) control of hyperparathyroidism by treatment with
calcium sensitizers (cinacalcet) [23, 24] , and (ii) improving solubility of calcium and
phosphate by sodium thiosulfate (STS) [25, 26]. This drug, known as antidote in cyanide
intoxication, was first used to prevent recurrence of calcium containing stones of the urinary
tract [27], then in tumoral calcinosis [28] and, more recently, has been used in calciphylaxis
[29, 30]. STS as a complexator of divalent ions may increase solubility of calcium phosphate
by formation of highly soluble calcium thiosulfate complexes and is able to chelate iron
that might play a role in the complex pathophysiology of calciphylaxis as has been recently
suggested [31]. STS has further been used to abrogate cisplatin toxicity, is an effective
antioxidant and reverses endothelial dysfunction by increased nitric oxide production [7].
Furthermore Pasch at al. could show in an animal experimental model that STS can prevent
vascular calcification [32]. In addition a vasoactive role by hydrogen sulfide generation has
been proposed [33, 34]. Knowledge about pharmacodynamics of STS have been published
recently [35].
Here we present five fully documented cases of calciphylaxis that were successfully
managed with a novel triple treatment combining oral cinacalcet, sevelamer and intravenous
STS, including long term treatment and survival data.
347
DOI: 10.1159/000350162
www.karger.com/kbr
Patients and Materials
Ethical considerations
All patients gave informed consent concerning off-label use of the drugs applied and concerning
scientific analysis of their data. This study was performed according to the Federal Laws and Regulations of
Austria and Germany and is in accordance with the ethical standards of the local Institutional Review Board
as well as adherent with the Helsinki Declaration of 1975, as revised in 2000.
Basic demographic data, comorbidities, classical cardiovascular risk factors, special risk factors
associated with calciphylaxis and initial laboratory values are depicted in Table 1.
Case 1
In January 2005 a 58 year old male presented at our emergency room with severe pain of his abdominal
wall and progressive immobilization. Abdominal subcutaneous adipose tissue was vastly indurated and
extremely painful even upon light touch. There was no skin necrosis. He was first treated for ten days with
broad spectrum antibiotics, since soft-tissue infection was suspected. No response, according to clinical
condition and inflammation markers, was achieved. Due to multiple risk factors, including an extremely
high parathyroid hormone (reported at >1200 pg/ml) a few weeks prior to admission, we suspected
non-necrotizing calciphylaxis. Sodium thiosulfate was applied ex juvantibus for several days prior to skin
biopsy to reduce the risk of biopsy site necrosis (see below); diagnosis was histopathologically ascertained.
Treatment included: the use of high doses of IV STS (80 g) and cinacalcet (300 mg) per day, replacement
of aluminum- and calcium-containing phosphate binders by sevelamer; intensive daily hemodiafiltration
(6 hours) against low calcium, replacement of coumadins by IV heparin, combined analgesic treatment,
treatment of acidosis by sodium bicarbonate, administration of calcitonin and IV ibandronate (2 mg
used once) and cessation of all subcutaneous drug administrations. The high initial doses of STS caused
hypernatremia, and metabolic acidosis. Furthermore, the patient developed a gastric ulcer hemorrhage and
one epileptic seizure.
Cinacalcet (initial dose: 300 mg per day), and sevelamer (initial dose: 4800 mg per day) had to be
paused after three weeks for approximately three weeks due to anorexia and resulting incompliance.
Cinacalcet was then reinitiated at 60 mg per day. STS was reduced to four times 30 g per week four weeks
after start of treatment and dialysis frequency was simultaneously reduced. No further side effects (such
as nausea, vomiting, seizures, hypernatremia, hemorrhage or acidosis) occurred after this dose reduction.
Within a few days from initiation of therapy, pain and inflammatory markers decreased and in the
course of weeks, the vast indurations of his abdomen slowly resolved.
After five months of treatment, severe erysipelas of his left leg and sepsis occurred. The patient needed
vasopressor treatment and intensive care management. After eight months, due to very low dietary and
drug compliance as well as increasing pruritus, parathyroidectomy was performed and cinacalcet was
stopped. A significant improvement of skin condition and pruritus resulted. After ten months he suffered
from pneumoccocal pneumonia and was on mechanical ventilation for three weeks.
Treatment with STS was never discontinued.
After one year of treatment, most of the subcutaneous indurations had vanished. The patient´s
condition had remarkably increased. He had lost 30 kg of weight (prior to the severe infectious complications
mentioned), did not need further insulin treatment and was well mobilized since four months after the start
of treatment. He then was in a good condition and continued to receive STS treatment, since minor (nonnecrotic) indurations of the skin never resolved. No further side effects occured.
After two years, upon dose reduction of STS from 30 g thrice weekly to 15 g thrice weekly, painful skin
necroses of the calves occurred. The dosage was re-increased to 30 g thrice weekly and the ulcers healed
within four weeks.
This patient died from sudden cardiac death following routine shunt surgery after having received
continuous treatment for 52 months.
Case 2
A 61 year old male had undergone subtotal parathyroidectomy two years earlier, when suffering
from a first attack of calciphylaxis on both calves. In February 2005 he presented with an extensive,
348
DOI: 10.1159/000350162
www.karger.com/kbr
inflamed, severely painful skin necrosis of his left calf. Administration of cinacalcet (due to recurrent
hyperparathyroidism) and switch from coumadin to heparin as well as intensification of dialysis treatment
had already been started two months earlier at his external dialysis unit with unsatisfactory results. Upon
admission to our hospital he was on coumadin treatment again. We continued cinacalcet and coumadin
(due to the risk of aortic valve thrombosis on heparin treatment) and started daily treatment with STS (40
g), sevelamer (2400 mg) and intensified the pain regimen. He needed antibiotic treatment due to purulent
infection of the necrosis. Careful wound management, avoiding tissue trauma was initiated. He was on
continuous intravenous STS treatment for six months, while reducing STS infusions and dialysis frequency
to three times a week after discharge. Due to anorexia and vomiting, STS dose was reduced to 25 g thrice
weekly after three months. His skin necrosis continuously improved and the wound completely healed six
months after initiation of STS treatment. From thereon, 10 g were administered twice a week and were
continued for another two months. This patient suffered from intermittent recurrence of ulcerations in 2006
and 2007. He did not consent to reinitiation of STS treatment while continuing cinacalcet and sevelamer.
He underwent percutaneous angioplasty in 2010 and was free of ulcerations since then. 84 months after
initiation of STS treatment the patient died due to cardiac reasons, but without active calciphylaxis.
Case 3
In October 2005, a 60 year old female presented with intolerable pain of her right calf and rapidly
progressive skin necrosis with secondary infection. Examination also revealed three ulcers of her left calf
that had developed two months earlier. Treatment was initiated with low calcium daily dialysis, cinacalcet
(30 mg per day) and STS (40 g per day). Antibiotic treatment was started due to purulent infection of the
necrosis. Subtle, atraumatic resection of small parts of the necrosis was done to enable drainage of the pus.
Within a few days, the primary necrosis increased in size despite treatment and her pain was difficult to
control. Several livid, painful subcutaneous indurations on both calves and thighs developed, yet no further
necrosis at these sites occurred. A continuous improvement was subsequently achieved. Eight weeks
after the first admission, parathyroidectomy was performed and cinacalcet was stopped, since oral drug
compliance was poor. Within six months of treatment, the leg ulcers were completely healed and and her
geneal condition was remarkably improved. In summary, the patient received continuous STS treatment for
16 months after which she requested that the treatment be stopped. Another six months later she died from
acute cardiac death, without recurrence of the disease.
Case 4
In June 2007, a 66 year old male patient presented with multiple, infected, painful ulcerations of both
calves, that had started five months earlier, and end-stage renal disease (unknown glomerular disease with
nephrotic range proteinuria) with edema and a pericardial effusion.
Hemodialysis treatment was initiated and a skin biopsy was performed. Calciphylaxis was diagnosed.
STS treatment (25 g thrice weekly) was initiated. Antibiotic treatment, had been started two weeks earlier
and was continued for another two weeks. In addition, calcium carbonate was changed to sevelamer. Since
the patient initially presented with uremic vomiting, cinacalcet was not prescribed first-line to reduce
combined side effects. Upon further increase of PTH levels, the patient took cinacalcet for several weeks,
but not over a prolonged period due to nausea. So in this patient, the contribution of cinacalcet to treatment
may have been fairly low, due to poor drug compliance.
The ulcers and degree of pain continuously improved within three weeks. The ulcers healed
within six months from start of treatment. Poor compliance concerning fluid restriction resulted in high
interdialytic weight gains (which were well tolerated), and continued calf edema. Although this might have
been aggravated by STS treatment, there was no change in interdialytic weight gains after cessation of STS
infusions. This patient was on STS treatment for fourteen months with gradual dose reduction after ten
months. Metabolic acidosis, requiring PO bicarbonate in addition to dialysis treatment was observed similar
as in Case 1.
This patient was disease-free ever since and died from heart failure in December 2009. A metastatic
colon cancer was found in autopsy.
349
DOI: 10.1159/000350162
www.karger.com/kbr
Case 5
In November 2007 a 61 year old male patient presented to the dermatology unit with a painful
ulcer of his left calf and was transferred to nephrology for suspected calciphylaxis. During the preceding
months, hypercalcemia had repeatedly been documented by his dialysis centre. In our view, this was due
to combined treatment of renal hyperparathyroidism with high doses of calcium-containing phosphate
binders and calcitriol.
Skin biopsy was performed; coumadin, calcitriol and calcium-containing phosphate binders were
discontinued. STS 25 g was administered thrice weekly after each hemodialysis treatment via his Cimino
shunt. Cinacalcet was initiated at 60 mg per day and sevelamer was started. An initial episode of nausea was
easily managed with metoclopramide. Furthermore, furosemide and calcitonin were administered for five
days to treat hypercalcemia. Calcium free dialysis solutions were used initially and changed to low calcium
after normalization of serum calcium levels.
Treatment was tolerated well with the only minor side effect being slight nausea. No changes of fluid,
electrolyte or acid-base-homeostasis were found. Pain decreased rapidly and the calf ulceration healed
within five months.
STS treatment was continued in decreasing doses for another six months and then stopped. No
recurrence of disease occurred. This patient underwent aortic and mitral valve replacement because of
endocarditis in October 2009. After an initially successful procedure, the patient developed recurrent
aspiration pneumonias and died, probably caused by sudden cardiac death, in December 2009. There was
no consent for autopsy.
Statistical methods
Descriptive statistics included computation of means and standard deviations. All analyses were done
using SPSS 20 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM
Corp.) and STATISTICA 10.0. (StatSoft, Inc. (2011). STATISTICA (data analysis software system), version 10.
www.statsoft.com).
Results
An overview of demographic variables, risk factors and co-morbidities is given in
Table 1, as well as a summary of characteristics of calciphylactic lesions (Table 1). A typical
course of wound healing is shown in Figure 1. The histopathological lesion of calciphylaxis,
calcification of small subcutaneous arterioles, is depicted in Figure 2.
Treatment measures and drug dosages, as well as overall STS treatment times, time to
wound healing, recurrence and survival data are shown in Table 2.
In 4 patients (all presenting with the necrotizing, distal type), a complete remission
was achieved and STS could be stopped. In 1 patient (severe, proximal, non-necrotizing
type) a partial (near-complete) remission was documented, since very minor subcutaneous
calcifications still could be found. Treatment was therefore continued for 52 months.
One and two year estimated survival probabilities were 100 % and 80 %, respectively.
Side effects of treatment are summarized in Table 3.
Laboratory values of calcium, phosphate, parathyroid hormone and bicarbonate in
course of multimodal treatment are depicted in Figure 3.
Discussion
Calciphylaxis is a severe disease with a high mortality of up to 81% and a median
survival of 2.64 months from the date of diagnosis [12]. Recently, with STS treatment Zitt et
al found a 50 % survival of 3.3 months [30]. Classical treatment recommendations include:
intensification of dialysis (increase of frequency and duration [20]) using a low calcium
dialysate [17]; cessation of vitamin D preparations as well as calcium containing phosphate
binders, steroids, immunosuppressants, blood products; application of bisphosphonates
350
DOI: 10.1159/000350162
www.karger.com/kbr
Table 1. Demographic variables, risk factors and comorbitidies at presentation. None of the patients revealed any signs of clinically relevant peripheral or cerebral artery disease at presentation
[18]. Yet all these measures did not substantially improve the grim outcome of the disease.
Since hyperparathyroidism seems to be one of the important factors in precipitating the
disease, emergency parathyroidectomy has frequently been performed [16].
Several years ago, cinacalcet, a calcium sensitizing agent, was introduced as a novel drug
to treat renal hyperparathyroidism [36]. Drug-induced decrease of PTH may circumvent
the complications of surgery and anesthesia under high risk conditions. In addition, bone
metabolism can be altered at will to target levels of PTH, whereas parathyroidectomy may
have irreversible results.
351
DOI: 10.1159/000350162
www.karger.com/kbr
Fig. 1. Calciphylaxis of the
left calf of Case
2. In the course
of six months
the extensive,
inflamed, severly painful skin
necrosis healed
completely.
A
B
C
baseline
2 months
4 months 6 months
Fig. 2. Histologic study of
the biopsied skin lesion
of Case 1. A: Photomicrograph showing calcium
deposits within the lumen of a small-sized vessel (arrow); B: von Kossa
staining was performed to
detect calcium deposits;
brown-staining areas indicate calcium deposition
(arrows).
A
B
HE
von Kossa
D
In a case report prior to our first patient, STS was used to treat calciphylaxis [25].
Since then, a series of case reports has been published [26, 29, 37, 38]. Recently, we have
participated in a study including 27 calciphylaxis patients receiving STS treatment, which
showed a trend towards prolonged survival [30]. STS might dissolve calcium phosphate
precipitates by formation of highly soluble calcium thiosulfate complexes [29, 32, 39]. This
solubilising effect had been postulated earlier to result in the prevention of recurrence of
calcium containing urinary stones [27] and of calcium deposits in tumoral calcinosis [28] as
well as nephrocalcinosis [40].
These concepts of drug effect have been challenged by in vitro experiments of O´Neill
and Hardcastle [41]. Thus, the exact mechanism of STS still remains elusive.
Here we present a novel concept to treat calciphylaxis. We believe that no single measure
can sufficiently improve the outcome of this disease. Yet control of hyperphosphatemia
and hyperparathyroidism and – as the most important measure – treatment with IV STS
to improve solubility of the calcium-phosphate complex seem to give a realistic chance to
significantly improve the prognosis of this devastating disease.
No standard dose of STS has yet been established. In our series, a wide range of doses
was used. Generally, at least in cases of moderate disease activity and patients of average
weight, a 25 g dose three times per week seems to be sufficient in the maintenance phase.
This is in accordance with earlier case reports [25, 26, 38] and the data by Zitt et al [30],
who reported an STS dosing range of 30 to 125 g per week with 81 % of patients receiving
75 (3 x 25) g per week. Similarly, 25 g/1.73 m2 body surface area have been administered
352
DOI: 10.1159/000350162
www.karger.com/kbr
Table 2. Treatment measures and survival times; recurrence and death related to disease
in pediatric patients [42]. In desperate cases, up to 80 g per day can be applied under close
monitoring of fluid, electrolyte and acid-base equilibrium, as performed in patient 1. Since a
significant increase in side effects with high doses (see Table 3) can be expected, we would
advise to start with lower doses (e.g. 25 g), consider disease severity and body mass index
for initial dose estimation (see Table 2) and perform a dose titration according to clinical
effect and tolerability.
353
DOI: 10.1159/000350162
www.karger.com/kbr
Major treatment goals aim at decreasing the risk of calcium phosphate precipitation
(i) decreasing the calcium phosphate load (stop calcium containing phosphate binders
and vitamin D; decrease oral phosphate uptake by dietary restriction and sevelamer; use
low-calcium dialysate; increase dialysis intensity by daily, long-term dialysis).
(ii) decreasing hyperparathyroidism (using cinacalcet or surgical parathyroidectomy;
yet the optimum target range of parathyroid hormone in calciphylaxis is currently unknown;
PTH management should consider the risk of adynamic bone),
(iii) decreasing bone demineralization (e.g, treatment of renal acidosis). The use of
bisphosphonates remains controversial.
(iv) administering STS, which, among other effects, may possibly increase the solubility
of the calcium-phosphate complex.
Additional measures
(v) careful wound management avoiding trauma and performing subtle surgery
primarily only in infection (there is a substantial risk of progressive necrosis at each new
trauma site of ischemic skin [own unpublished data]; this must be kept in mind despite
favourable reports of aggressive wound care, see [12, 20, 43]).
(vi) early treatment of infections (antibiotics, wound management),
(vii) effective pain management,
(viii) cessation of coumadins (which inactivate vitamin K dependent tissue inhibitors
of calcification, such as matrix GLA protein) and, possibly, supplementation of vitamin K2.
Our new concept combines treatment of hyperparathyroidism by cinacalcet, improving
calcium-phosphate solubility by STS and phosphate control by a non-calcium-non-aluminum
phosphate binder (sevelamer). In addition to this, a high dialysis intensity (e.g., starting
with 6 hours of treatment daily) and low dialysate calcium concentration, treatment of
renal acidosis with sodium bicarbonate where needed, intensive analgesic and antiemetic
treatment, careful and subtle wound management, avoidance of tissue trauma (including
subcutaneous injections and surgery, if at all possible), early targeted antibiotic treatment (if
infection should occur) and cessation of coumadins are necessary.
Need of parathyroidectomy should be re-evaluated regularly and should be considered
(i) if no improvement should occur, (ii) if drug side effects of cinacalcet are intolerable and
(iii) if compliance is poor. This is particularly important, since cinacalcet may cause severe
gastrointestinal side effects, including anorexia and vomiting.
In our view, the use of bisphosphonates, as performed in case 1, should no longer be
generally recommended, despite anecdotal reports of beneficial effects in calciphylaxis [18,
44]. This is due to the detrimental effects of bisphosphonates on uremic bone, which may
result in adynamic bone disease and aggravation of calcium-phosphate disorder by blocking
the buffering capacity of bone.
Table 3. Side effects of sodium thiosulfate
Fig. 3. Laboratory values
of calcium and phosphate
as well as parathyroid hormone and bicarbonate in
time course of multimodal
treatment.
354
DOI: 10.1159/000350162
www.karger.com/kbr
355
DOI: 10.1159/000350162
www.karger.com/kbr
As cases 2 (ineffective treatment with cinacalcet prior to combination with sodiumthiosulfate) and 4 (no long-term effective dose of cinacalcet achieved due to low drug
compliance) demonstrate, the most important single measure in management of calciphylaxis
is STS treatment.
Additionally, our results show that IV STS can be used even for years without major side
effects.
As the study by Zitt et al pointed out, STS as single measure may not be effective in
all cases: 52 % of patients showed a complete remission and 70 % a partial or complete
remission; 52 % of patients died after 101 days (3.3 months) [30]. Earlier studies reported
one-year mortality rates of 45 – 55 % [12, 45].
The patients in this series were younger (60.8 vs 68 years) and had a higher dialysis
vintage, (29.8 vs 12.4 months) when compared to the study by Zitt et al., whereas the comorbidities were rather similar. They received higher initial STS doses (also due to increased
dialysis frequency) and prolonged treatment times (20 vs 3.3 months).
Our five patients had a complete remission rate of 80 % and a complete or partial
remission rate of 100 %. Similarly, the one- and two-year survival was 100 % and 80 %
respectively.
To our knowledge, there is no clinical evidence in humans concerning a possible bone
demineralising effect of STS or a potential increase in fracture rates. At least our patients despite long term STS use - did not reveal any treatment-associated bone problems.
Clearly, our study has several limitations: Firstly, case number is low, as with any rare
disease. Secondly, since patient recruitment was performed over several years, paradigm
changes in calcium phosphate management have taken place and may have influenced target
levels in our patients. Suppression of PTH or parathyroidectomy was considered beneficial
at the beginning of our series to effectively control calcium phosphate metabolism. This may
still be evaluated depending on the severity and refractoriness of calcium and phosphate
derangements. Calciphylaxis patients may present with persistent hyperparathyroidism or
with development of adynamic bone. STS treatment, on the other hand, tends to increase
PTH (personal, unpublished observation). As a limitation of our results, use of cinacalcet is
not encouraged in development of adynamic bone. Thirdly, not one drug used in isolation
was proven to be effective. Despite a synergistic approach, not all patients could be treated
with all three drugs continuously, due to side effects as well as patient incompliance. Yet
these problems reflect the general complexity of severely ill, multi-morbid patients. We do
not suppose, it will be possible to perform a randomized, placebo-controlled trial in such a
rare and devastating disease as calciphylaxis in the near future.
Conclusion
We believe, that calciphylaxis has lost some of its threat. It still is a potentially lethal
disease, requiring intensive and combined treatments. Evaluation of risk factors and early
diagnosis of this disease should be encouraged. Since therapeutic measures minimising the
risk of wound necrosis are available now, deep skin biopsy at the site of the suspected deep
subcutaneous vessel (i.e. not at the ulcer margin, but at the estimated “circle midpoint of the
supplying vessel”) should be encouraged. A combined treatment of cinacalcet (in cases with
severe hyperparathyroidism), sevelamer and STS, as well as subtle, non-traumatic wound
management, can increase patient survival.
In our five patients, one and two year survival was 100% and 80%, respectively. Survival
times since initiation of dialysis reported here were in accordance with the general outcome
of hemodialysis patients. This demonstrates the efficacy of the proposed treatment (see:
Excerpts from the US Renal Data System 2009, Annual Data Report: 54 months for this age
group [46]; and analysis of the Austrian Dialysis and Transplant Registry (OEDTR): median
survival data (2005-2007) of incident hemodialysis patients, age group of 55 to 65 years:
56.9 months; [47].
356
DOI: 10.1159/000350162
www.karger.com/kbr
The data reported here were provided by OEDTR. Responsibility for interpretation and
reporting of these data lies with the authors).
Conflict of Interests
H.S. has received unrestricted research grants by Amgen Corp. and has received lecture
honoraria from Amgen Corp, Roche Austria, Fresenius Medical Care and Genzyme. All other
authors have declared no conflict of interest.
Acknowledgements
The support of Dr. Reinhard Kramar, Austrian Dialysis and Transplant Registry
(OEDTR), providing survival data, is gratefully acknowledged. Proof-reading the manuscript
by Jennifer Raschauer, MD, and Neil Jones, MD, is gratefully acknowledged.
References
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Brandenburg VM, Kramann R, Specht P, Ketteler M: Calciphylaxis in CKD and beyond. Nephrol Dial
Transplant 2012;27:1314-1318.
Asobie N, Wong E, Cook MG: Calciphylaxis in a diabetic patient provoked by warfarin therapy. Clin Exp
Dermatol 2008;33:342-344.
Nigwekar SU, Wolf M, Sterns RH, Hix JK: Calciphylaxis from nonuremic causes: a systematic review. Clin J
Am Soc Nephrol 2008;3:1139-1143.
Hayashi M, Takamatsu I, Kanno Y, Yoshida T, Abe T, Sato Y, Japanese Calciphylaxis Study G: A case-control
study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant 2012;27:15801584.
Au S, Crawford RI: Three-dimensional analysis of a calciphylaxis plaque: clues to pathogenesis. J Am Acad
Dermatol 2002;47:53-57.
Weenig RH: Pathogenesis of calciphylaxis: Hans Selye to nuclear factor kappa-B. J Am Acad Dermatol
2008;58:458-471.
Rogers NM, Coates PT: Calcific uraemic arteriolopathy: an update. Curr Opin Nephrol Hypertens
2008;17:629-634.
Hussein MR, Ali HO, Abdulwahed SR, Argoby Y, Tobeigei FH: Calciphylaxis cutis: a case report and review of
literature. Exp Mol Pathol 2009;86:134-135.
Suryadevara M, Schurman SJ, Landas SK, Philip A, Gerlach CB, Tavares T, Souid AK: Systemic calciphylaxis.
Pediatr Blood Cancer 2008;51:548-550.
Mochel MC, Arakaki RY, Wang G, Kroshinsky D, Hoang MP: Cutaneous Calciphylaxis: A Retrospective
Histopathologic Evaluation. Am J Dermatopathol 2013; DOI 10.1097/DAD.0b013e31827c7f5d.
Elamin EM, McDonald AB: Calcifying panniculitis with renal failure: a new management approach.
Dermatology 1996;192:156-159.
Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR: Calciphylaxis: natural history, risk factor
analysis, and outcome. J Am Acad Dermatol 2007;56:569-579.
Brandenburg VM, Cozzolino M, Ketteler M: Calciphylaxis: a still unmet challenge. J Nephrol 2011;24:142148.
Wu M, Rementer C, Giachelli CM: Vascular Calcification: An Update on Mechanisms and Challenges in
Treatment. Calcif Tissue Int 2013; DOI 10.1007/s00223-013-9712-z.
Guldbakke KK, Khachemoune A: Calciphylaxis. Int J Dermatol 2007;46:231-238.
357
DOI: 10.1159/000350162
www.karger.com/kbr
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Girotto JA, Harmon JW, Ratner LE, Nicol TL, Wong L, Chen H: Parathyroidectomy promotes wound healing
and prolongs survival in patients with calciphylaxis from secondary hyperparathyroidism. Surgery
2001;130:645-650; discussion 650-641.
Lipsker D, Chosidow O, Martinez F, Challier E, Frances C: Low-calcium dialysis in calciphylaxis. Arch
Dermatol 1997;133:798-799.
Monney P, Nguyen QV, Perroud H, Descombes E: Rapid improvement of calciphylaxis after intravenous
pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant 2004;19:2130-2132.
Swanson AM, Desai SR, Jackson JD, Andea AA, Hughey LC: Calciphylaxis associated with chronic
inflammatory conditions, immunosuppression therapy, and normal renal function: a report of 2 cases. Arch
Dermatol 2009;145:723-725.
Russell R, Brookshire MA, Zekonis M, Moe SM: Distal calcific uremic arteriolopathy in a hemodialysis
patient responds to lowering of Ca x P product and aggressive wound care. Clin Nephrol 2002;58:238-243.
Alikadic N, Kovac D, Krasna M, Lindic J, Sabovic M, Tomazic J, Jeras M, Smrke D: Review of calciphylaxis
and treatment of a severe case after kidney transplantation with iloprost in combination with hyperbaric
oxygen and cultured autologous fibrin-based skin substitutes. Clin Transplant 2009;23:968-974.
Lal G, Nowell AG, Liao J, Sugg SL, Weigel RJ, Howe JR: Determinants of survival in patients with
calciphylaxis: a multivariate analysis. Surgery 2009;146:1028-1034.
Velasco N, MacGregor MS, Innes A, MacKay IG: Successful treatment of calciphylaxis with cinacalcet-an
alternative to parathyroidectomy? Nephrol Dial Transplant 2006;21:1999-2004.
Sharma A, Burkitt-Wright E, Rustom R: Cinacalcet as an adjunct in the successful treatment of calciphylaxis.
Br J Dermatol 2006;155:1295-1297.
Cicone JS, Petronis JB, Embert CD, Spector DA: Successful treatment of calciphylaxis with intravenous
sodium thiosulfate. Am J Kidney Dis 2004;43:1104-1108.
Brucculeri M, Cheigh J, Bauer G, Serur D: Long-term intravenous sodium thiosulfate in the treatment of a
patient with calciphylaxis. Semin Dial 2005;18:431-434.
Yatzidis H: Successful sodium thiosulphate treatment for recurrent calcium urolithiasis. Clin Nephrol
1985;23:63-67.
Kyriakopoulos G, Kontogianni K: Sodium thiosulfate treatment of tumoral calcinosis in patients with endstage renal disease. Ren Fail 1990;12:213-219.
Schlieper G, Brandenburg V, Ketteler M, Floege J: Sodium thiosulfate in the treatment of calcific uremic
arteriolopathy. Nat Rev Nephrol 2009;5:539-543.
Zitt E, Konig M, Vychytil A, Auinger M, Wallner M, Lingenhel G, Schilcher G, Rudnicki M, Salmhofer H, Lhotta
K: Use of sodium thiosulphate in a multi-interventional setting for the treatment of calciphylaxis in dialysis
patients. Nephrol Dial Transplant 2013; DOI 10.1093/ndt/gfs548
Farah M, Crawford RI, Levin A, Chan Yan C: Calciphylaxis in the current era: emerging ‘ironic’ features?
Nephrol Dial Transplant 2011;26:191-195.
Pasch A, Schaffner T, Huynh-Do U, Frey BM, Frey FJ, Farese S: Sodium thiosulfate prevents vascular
calcifications in uremic rats. Kidney Int 2008;74:1444-1453.
Roy A, Khan AH, Islam MT, Prieto MC, Majid DS: Interdependency of cystathione gamma-lyase and
cystathione beta-synthase in hydrogen sulfide-induced blood pressure regulation in rats. Am J Hypertens
2012;25:74-81.
Zavaczki E, Jeney V, Agarwal A, Zarjou A, Oros M, Katko M, Varga Z, Balla G, Balla J: Hydrogen sulfide inhibits
the calcification and osteoblastic differentiation of vascular smooth muscle cells. Kidney Int 2011;80:731739.
Farese S, Stauffer E, Kalicki R, Hildebrandt T, Frey BM, Frey FJ, Uehlinger DE, Pasch A: Sodium thiosulfate
pharmacokinetics in hemodialysis patients and healthy volunteers. Clin J Am Soc Nephrol 2011;6:14471455.
Block GA, Martin KJ, de Francisco AL, Turner SA, Avram MM, Suranyi MG, Hercz G, Cunningham J, AbuAlfa AK, Messa P, Coyne DW, Locatelli F, Cohen RM, Evenepoel P, Moe SM, Fournier A, Braun J, McCary LC,
Zani VJ, Olson KA, Drueke TB, Goodman WG: Cinacalcet for secondary hyperparathyroidism in patients
receiving hemodialysis. N Engl J Med 2004;350:1516-1525.
358
DOI: 10.1159/000350162
www.karger.com/kbr
37
38
39
40
41
42
43
44
45
46
47
Musso CG, Enz P, Vidal F, Gelman R, Lizarraga A, Giuseppe LD, Kowalczuk A, Garfi L, Galimberti R, Algranati
L: Use of sodium thiosulfate in the treatment of calciphylaxis. Saudi J Kidney Dis Transpl 2009;20:10651068.
Guerra G, Shah RC, Ross EA: Rapid resolution of calciphylaxis with intravenous sodium thiosulfate and
continuous venovenous haemofiltration using low calcium replacement fluid: case report. Nephrol Dial
Transplant 2005;20:1260-1262.
O’Neill WC: Treatment of vascular calcification. Kidney Int 2008;74:1376-1378.
Agroyannis B, Tzanatos H, Vlahakos DV, Mallas E: Does long-term administration of sodium thiosulphate
inhibit progression to renal failure in nephrocalcinosis? Nephrol Dial Transplant 2001;16:2443-2444.
O’Neill WC, Hardcastle KI: The chemistry of thiosulfate and vascular calcification. Nephrol Dial Transplant
2012;27:521-526.
Araya CE, Fennell RS, Neiberger RE, Dharnidharka VR: Sodium thiosulfate treatment for calcific uremic
arteriolopathy in children and young adults. Clin J Am Soc Nephrol 2006;1:1161-1166.
Sato T, Ichioka S: How should we manage multiple skin ulcers associated with calciphylaxis? J Dermatol
2012;39:966-968.
Torregrosa JV, Duran CE, Barros X, Blasco M, Arias M, Cases A, Campistol JM: Successful treatment of calcific
uraemic arteriolopathy with bisphosphonates. Nefrologia 2012;32:329-334.
Fine A, Zacharias J: Calciphylaxis is usually non-ulcerating: risk factors, outcome and therapy. Kidney Int
2002;61:2210-2217.
Collins AJ, Foley RN, Herzog C, Chavers BM, Gilbertson D, Ishani A, Kasiske BL, Liu J, Mau LW, McBean
M, Murray A, St Peter W, Guo H, Li Q, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C,
Weinhandl E, Zaun D, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C,
Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers PW, Agodoa L: Excerpts from the
US Renal Data System 2009 Annual Data Report. Am J Kidney Dis 2010;55:S1-420, A426-427.
Kramar R, Oberbauer R: Austrian dialysis and transplant registry (oedtr), annual report 2012. www.
nephro.at, Austrian Society of Nephrology, 2012.
359

Multi-Modal Treatment Of Calciphylaxis With Sodium

Transcription

Similar documents

Public summary of opinion on orphan designation

INTRODUCTION

Get Started - Tiens Family

Jumbo Christmas Stocking

Gecko Frecko

We have the solution Electronic Scale Protection

Spirit Newsletter - St. Timothy`s School

Supporting Biodiversity

Yarn FREE Knit Textured Cloths Pattern

Spring 2010 Spirit Newsletter

Australia`s Premium Hunting Website

Event Postcard